Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 450
Страница 64 из 545-
Brain organoid models for studying the function of iPSC-derived microglia in neurodegeneration and brain tumours.
Microglia represent the main resident immune cells of the brain. The interplay between microglia and other cells in the central nervous system, such as neurons or other glial cells, influences the function and ability of microglia to respond to various stimuli. These cellular communications, when disrupted, can affect the structure and function of the brain, and the initiation and progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as the progression of other brain diseases like glioblastoma. Due to the difficult access to patient brain tissue and the differences reported in the murine models, the available models to study the role of microglia in disease progression are limited. Pluripotent stem cell technology has facilitated the generation of highly complex models, allowing the study of control and patient-derived microglia in vitro. Moreover, the ability to generate brain organoids that can mimic the 3D tissue environment and intercellular interactions in the brain provide powerful tools to study cellular pathways under homeostatic conditions and various disease pathologies. In this review, we summarise the most recent developments in modelling degenerative diseases and glioblastoma, with a focus on brain organoids with integrated microglia. We provide an overview of the most relevant research on intercellular interactions of microglia to evaluate their potential to study brain pathologies.
-
Early-life exposure to polypropylene nanoplastics induces neurodevelopmental toxicity in mice and human iPSC-derived cerebral organoids.
Nanoplastics (NPs) are emerging environmental pollutants that pose growing concerns due to their potential health risks. However, the effects of inhaled NP exposure during pregnancy on fetal brain development remain poorly understood. In this study, we investigated the impact of maternal exposure to polypropylene nanoplastics (PP-NPs) on fetal brain development and neurobehavioral outcomes in a mouse model and further explored its mechanism in human cerebral organoids. Maternal exposure to PP-NPs significantly impaired neuronal differentiation and proliferation in the fetal cortex. Neurobehavioral assessments revealed significant deficits in offspring following maternal exposure, including impaired spatial memory, reduced motor coordination, and heightened anxiety-like behavior. Furthermore, human brain organoids exposed to PP-NPs exhibited reduced growth and neuronal differentiation, with significant downregulation of key neuronal markers such as TUJ1, MAP2, and PAX6. Transcriptomic analysis identified alterations in gene expression, particularly in neuroactive ligand-receptor interaction pathway. Molecular docking and fluorescence co-localization analysis further suggested CYSLTR1 and PTH1R as key molecular targets of PP-NPs. These findings provide novel insights into the toxicological effects of NPs on the developing brain and emphasize the need for preventive measures to protect fetal neurodevelopment during pregnancy.
-
"Archealization" of human brain organoids.
-
Analytic Models of Oxygen and Nutrient Diffusion, Metabolism Dynamics, and Architecture Optimization in Three-Dimensional Tissue Constructs with Applications and Insights in Cerebral Organoids.
Diffusion models are important in tissue engineering as they enable an understanding of gas, nutrient, and signaling molecule delivery to cells in cell cultures and tissue constructs. As three-dimensional (3D) tissue constructs become larger, more intricate, and more clinically applicable, it will be essential to understand internal dynamics and signaling molecule concentrations throughout the tissue and whether cells are receiving appropriate nutrient delivery. Diffusion characteristics present a significant limitation in many engineered tissues, particularly for avascular tissues and for cells whose viability, differentiation, or function are affected by concentrations of oxygen and nutrients. This article seeks to provide novel analytic solutions for certain cases of steady-state and nonsteady-state diffusion and metabolism in basic 3D construct designs (planar, cylindrical, and spherical forms), solutions that would otherwise require mathematical approximations achieved through numerical methods. This model is applied to cerebral organoids, where it is shown that limitations in diffusion and organoid size can be partially overcome by localizing metabolically active cells to an outer layer in a sphere, a regionalization process that is known to occur through neuroglial precursor migration both in organoids and in early brain development. The given prototypical solutions include a review of metabolic information for many cell types and can be broadly applied to many forms of tissue constructs. This work enables researchers to model oxygen and nutrient delivery to cells, predict cell viability, study dynamics of mass transport in 3D tissue constructs, design constructs with improved diffusion capabilities, and accurately control molecular concentrations in tissue constructs that may be used in studying models of development and disease or for conditioning cells to enhance survival after insults like ischemia or implantation into the body, thereby providing a framework for better understanding and exploring the characteristics and behaviors of engineered tissue constructs.
-
Brain assembloids decode human cortical networks in Rett syndrome.
Tenreiro et al.1 employ human cerebral organoids and telencephalic assembloids to reveal that MeCP2 deficiency leads to multiple defects in the formation of cortical neuronal networks during early prenatal brain development, offering new insights into the pathology of Rett syndrome.
-
A Model of Traumatic Brain Injury Oligomerizes Tau in Cortical Organoids and Induces Clinically Relevant Pathologies that Synergize with MAPT Mutation.
Traumatic brain injury (TBI) is the most important environmental risk factor for neurodegenerative disease. Tauopathy plays an important role in post-traumatic neurodegeneration. Human-induced pluripotent stem cell (hiPSC)-derived cortical organoids have exciting potential to reveal the influence of genotype on post-traumatic neurodegeneration because they permit manipulation of the genome in a human system. This study established an isogenic 3D cortical organoid model of TBI to investigate tau pathology and other clinically relevant injury phenotypes. Organoids generated from patient-derived hiPSC lines carrying the V337M or IVS10 + 16 Microtubule associated protein tau (MAPT) mutations and their clustered regularly interspaced short palindromic repeats (CRISPR)-corrected isogenic counterparts were subjected to consistent compressive injury. Mitochondrial dysfunction, cell viability, lactate dehydrogenase (LDH) release, neurofilament light chain (NF-L) release, tau hyperphosphorylation, and tau oligomerization were quantified using live-cell imaging, ELISA, Western blotting, and immunostaining post-injury. Pathology depended on the severity of the mechanical injury and the time since injury. The V337M mutation synergized with injury to exacerbate cell damage, increasing LDH release and reducing viability in 4- and 6-month-old organoids. Therefore, this model can reproduce gene-trauma interactions in vitro, so it has the capacity to answer important questions about why different patients have different outcomes after similar TBIs. MAPT mutation was not necessary for injury to induce tau hyperphosphorylation in 4-month-old organoids and both tau hyperphosphorylation and tau oligomerization in 6-month-old organoids. This capacity to induce advanced tau pathology in wild-type human organoids could have utility beyond the field of TBI research.
-
Graphene-polymer nanofibers enable optically induced electrical responses in stem cell-derived electrically excitable cells and brain organoids.
Human pluripotent stem cell (hPSC)-derived electrically excitable cells provide a unique window into development, but they remain electrically immature partially due to the lack of chronic stimulation. Here, we fabricated electrospun polymer nanofibers containing light-reactive reduced graphene oxide (rGO) as part of a new classes of on-demand, electrically active biomaterials to enhance cell function. Fiber size, stiffness, and electrical conductivity varied with rGO concentration, which impacted hPSC-derived cardiomyocyte and neuron responses; with acute light stimulation, cardiomyocytes exhibited increased, synchronous calcium handling. Long-term, daily nanofiber light stimulation improves brain organoid electrical activity and activates photoreceptor pathways. This work outlines a tunable method where electrical cell functions can be titrated with rGO fibers and light stimulation, and it suggests that repetitive light stimulation may provide a novel method for retinal differentiation.
-
Functional Divergence of NOTCH1 and NOTCH2 in Human Cerebral Organoids Reveals Receptor-Specific Roles in Early Corticogenesis.
The Notch signaling pathway is a critical regulator of embryonic brain development. Among its four mammalian receptors, Notch1 and Notch2 are particularly significant in the developing cortex, yet their roles in human neurodevelopment are not well understood. In murine cortex development, Notch1 primarily regulates early progenitor identity and neurogenesis, while Notch2 is required for maintaining radial glial cells at later stages. However, it is unclear whether these functions are conserved in the human developing brain. In this study, we used cerebral organoids as an in vitro model of early human corticogenesis and conducted lentiviral shRNA-mediated knockdowns of NOTCH1 and NOTCH2. Our findings indicate that NOTCH1 is essential for organoid growth, lumen morphogenesis, radial glial identity, and progenitor proliferation. In contrast, depleting NOTCH2 did not significantly affect these early developmental processes. These results demonstrate that NOTCH1 and NOTCH2 have potentially non-redundant and temporally distinct roles in early human corticogenesis, reflecting receptor-specific specialization within the Notch signaling pathway.
-
Human cortical organoids recapitulate inter-individual variability in infant brain-growth trajectories.
Induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) model neurogenesis on an individual's genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from whom they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who underwent longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of hem/choroid plexus were associated with in vivo cortical growth rates. Cell-cycle-associated gene expression in early progenitors at the crux of fate-decision trajectories was correlated with cortical growth rates from 6 to 12 months of age and was enriched for microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types that influences infant cortical surface area expansion.
-
Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression.
Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM samples. Integrative single-cell trajectory analysis of both eGBO-derived tumor cells and patient GBM samples reveal the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.